This invention relates to benzimidazole compounds and their pharmaceutically acceptable salts, and pharmaceutical compositions containing such compounds. These compounds and compositions have cyclooxygenase-2 inhibitory activities, therefore they are useful as agents for treatment of inflammatory diseases of a mammalian subject, especially a human subject.
Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used in treating pain and the signs and symptoms of arthritis because of their analgesic and anti-inflammatory activity. It is accepted that common NSAIDs work by blocking the activity of cyclooxygenase (COX), also known as prostaglandin G/H synthase (PGHS), the enzyme that converts arachidonic acid into prostanoids. Prostaglandins, especially prostaglandin E2 (PGE2), which is the predominant eicosanoid detected in inflammation conditions, are mediators of pain, fever and other symptoms associated with inflammation. Inhibition of biosynthesis of prostaglandins has been a therapeutic target of anti-inflammatory drug discovery. The therapeutic use of conventional NSAIDs is, however, limited due to drug associated side effects, including life threatening ulceration and renal toxicity. An alternative to NSAIDs is the use of corticosteriods, however, long tern therapy can also result in severe side effects. Recently, two forms of COX were identified, a constitutive isoform (COX-1) and an inducible isoform (COX-2) of which expression is upregulated at sites of inflammation (Vane, J. R.; Mitchell, J. A.; Appleton, I.; Tomlinson, A.; Bishop-Bailey, D.; Croxtoll, J.; Willoughby, D. A. Proc. Natnl. Acad. Sci. USA, 1994, 91, 2046). COX-1 is thought to play a physiological role and to be responsible for gastrointestinal and renal protection. On the other hand, COX-2 appears to play a pathological role and to be the predominant isoform present in inflammation conditions. A pathological role for prostaglandins has been implicated in a number of human disease states including rheumatoid and osteoarthritis, pyrexia, asthma, bone resorption, cardiovascular diseases, nephrotoxicity, atherosclerosis, hypotension, shock, pain, cancer, and Alzheimer disease. The NSAIDs currently on market inhibit both isoforms of COX with little variation for selectivity, explaining their beneficial (inhibition of COX-2) and deleterious effects (inhibition of COX-1). It is believed that compounds that would selectively inhibit the biosynthesis of prostaglandins by intervention of the induction phase of the inducible enzyme cyclooxygenase-2 and/or by intervention of the activity of the enzyme cyclooxygenase-2 on arachidonic acid would provide alternate therapy to the use of NSAIDs or corticosteriods in that such compounds would exert anti-inflammatory effects without the adverse side effects associated with COX-1 inhibition.
A variety of imidazole compounds are known and are disclosed in several patent applications. Specifically, Japanese Kokai (laid-open) Publication number S49-81369 discloses 1-benzyl-benzimidazole compounds as anti-inflammatory agents. Japanese Kokai (laid-open) Publication Number S59-75257 and H06-194780 disclose a variety of benzimidazole compounds as electrophotographic materials.
The present invention provides a compound of the following formula (I): 
or a pharmaceutically acceptable salt thereof, wherein
Ar is heteroaryl selected from
a 5-membered monocyclic aromatic ring having one hetero atom selected from O, S and N and optionally containing one to three N atom(s) in addition to said hetero atom, or
a 6-membered monocyclic aromatic ring having one N atom and optionally containing one to four N atom(s) in addition to said N atom; and
said heteroaryl being connected to the nitrogen atom on the benzimidazole through a carbon atom on the heteroaryl ring;
X1 is independently selected from halo, C1-C4 alkyl, hydroxy, C1-C4 alkoxy, halo-substituted C1-C4 alkyl, hydroxy-substituted C1-C4 alkyl, (C1-C4 alkoxy)C1-C4 alkyl, halo-substituted C1-C4 alkoxy, amino, Nxe2x80x94(C1-C4 alkyl)amino, N,N-di(C1-C4 alkyl)amino, [Nxe2x80x94(C1-C4 alkyl)amino]C1-C4 alkyl, [N,N-di(C1-C4 alkyl)amino]C1-C4 alkyl, Nxe2x80x94(C1-C4 alkanoyl)amino, Nxe2x80x94(C1-C4 alkyl)(C1-C4 alkanoyl)amino, Nxe2x80x94[(C1-C4 alkyl)sulfonyl]amino, N-[(halo-substituted C1-C4 alkyl)sulfonyl]amino, C1-C4 alkanoyl, carboxy, (C1-C4 alkoxy)carbonyl, carbamoyl, [Nxe2x80x94(C1-C4 alkyl)amino]carbonyl, [N,N-di(C1-C4 alkyl)amino]carbonyl, cyano, nitro, mercapto, (C1-C4 alkyl)thio, (C1-C4 alkyl)sulfinyl, (C1-C4 alkyl)sulfonyl, aminosulfonyl, [Nxe2x80x94(C1-C4 alkyl)amino]sulfonyl and [N,N-di(C1-C4 alkyl)amino]sulfonyl;
X2 is independently selected from halo, C1-C4 alkyl, hydroxy, C1-C4 alkoxy, halo-substituted C1-C4 alkyl, hydroxy-substituted C1-C4 alkyl, (C1-C4 alkoxy)C1-C4 alkyl, halo-substituted C1-C4 alkoxy, amino, Nxe2x80x94(C1-C4 alkyl)amino, N,N-di(C1-C4 alkyl)amino, [Nxe2x80x94(C1-C4 alkyl)amino]C1-C4 alkyl, [N,N-di(C1-C4 alkyl)amino]C1-C4 alkyl, Nxe2x80x94(C1-C4 alkanoyl)amino, Nxe2x80x94(C1-C4 alkyl)xe2x80x94Nxe2x80x94(C1-C4 alkanoyl) amino, Nxe2x80x94[(C1-C4 alky)sulfonyl]amino, N-[(halo-substituted C1-C4 alkyl)sulfonyl]amino, C1-C4 alkanoyl, carboxy, (C1-C4 alkoxy)carbonyl, carbamoyl, [Nxe2x80x94(C1-C4 alkyl)amino]carbonyl, [N,N-di(C1-C4 alkyl)amino]carbonyl, N-carbamoylamino, cyano, nitro, mercapto, (C1-C4 alkyl)thio, (C1-C4 alkyl)sulfinyl, (C1-C4 alkyl)sulfonyl, aminosulfonyl, [Nxe2x80x94(C1-C4 alkyl)amino]sulfonyl and [N,N-di(C1-C4 alkyl)amino]sulfonyl;
R1 is selected from
hydrogen;
straight or branched C1-C4 alkyl optionally substituted with one to three substituent(s) wherein said substituents are independently selected from halo, hydroxy, C1-C4 alkoxy, amino, Nxe2x80x94(C1-C4 alkyl)amino and N,N-di(C1-C4 alkyl)amino;
C3-C8 cycloalkyl optionally substituted with one to three substituent(s) wherein said substituents are independently selected from halo, C1-C4 alkyl, hydroxy, C1-C4 alkoxy, amino, Nxe2x80x94(C1-C4 alkyl)amino and N,N-di(C1-C4 alkyl)amino;
C4-C8 cycloalkenyl optionally substituted with one to three substituent(s) wherein said substituents are independently selected from halo, C1-C4 alkyl, hydroxy, C1-C4 alkoxy, amino, Nxe2x80x94(C1-C4 alkyl)amino and N,N-di(C1-C4 alkyl)amino;
phenyl optionally substituted with one to three substituent(s) wherein said substituents are independently selected from halo, C1-C4 alkyl, hydroxy, C1-C4 alkoxy, halo-substituted C1-C4 alkyl, hydroxy-substituted C1-C4 alkyl, (C1-C4 alkoxy)C1-C4 alkyl, halo-substituted C1-C4 alkoxy, amino, Nxe2x80x94(C1-C4 alkyl)amino, N,N-di(C1-C4 alkyl)amino, [Nxe2x80x94(C1-C4 alkyl)amino]C1-C4 alkyl, [N,N-di(C1-C4 alkyl)amino]C1-C4 alkyl, Nxe2x80x94(C1-C4 alkanoyl)amino, Nxe2x80x94[(C1-C4 alkyl)(C1-C4 alkanoyl)]amino, Nxe2x80x94[(C1-C4 alkyl)sulfonyl]amino, N-[(halo-substituted C1-C4 alkyl)sulfonyl]amino, C1-C4 alkanoyl, carboxy, (C1-C4 alkoxy)carbonyl, carbamoyl, [Nxe2x80x94(C1-C4 alkyl)amino]carbonyl, [N,N-di(C1-C4 alkyl)amino]carbonyl, cyano, nitro, mercapto, (C1-C4 alkyl)thio, (C1-C4 alkyl)sulfinyl, (C1-C4 alkyl)sulfonyl, aminosulfonyl, [Nxe2x80x94(C1-C4 alkyl)amino]sulfonyl and [N,N-di(C1-C4 alkyl)amino]sulfonyl; and
heteroaryl selected from
a 5-membered monocyclic aromatic ring having one hetero atom selected from O, S and N and optionally containing one to three N atom(s) in addition to said hetero atom; or
a 6membered monocyclic aromatic ring having one N atom and optionally containing one to four N atom(s) in addition to said N atom; and
said heteroaryl being optionally substituted with one to three substituent(s) selected from X1;
R2 and R3 are independently selected from:
hydrogen;
halo;
C1-C4 alkyl,
phenyl optionally substituted with one to three substituent(s) wherein said substituents are independently selected from halo, C1-C4 alkyl, hydroxy, C1-C4 alkoxy, amino, Nxe2x80x94(C1-C4 alkyl)amino and N,N-di(C1-C4 alkyl)amino;
or R1 and R2 can form, together with the carbon atom to which they are attached, a C3-C7-cycloalkyl ring;
m is 0, 1, 2, 3, 4 or 5; and
n is 0, 1, 2, 3 or 4.
The benzimidazole compounds of the present invention exhibit inhibition of COX activity. Preferably, compounds of present invention exhibit inhibitory activity against COX-2, in a COX-2 selective way. Therefore, this invention also relates to a pharmaceutical composition useful as anti-inflammatory agents and analgesics, which comprises a compound of this invention and a pharmaceutically acceptable carrier.
The present invention also relates to a pharmaceutical composition for treating a disorder or condition in a mammal, selected from rheumatoid and osteoarthritis, pyrexia, asthma, bone resorption, cardiovascular diseases, nephrotoxicity, atherosclerosis, hypotension, shock, pain, cancer, Alzheimer disease, and other disorders and conditions, in which a pathological role of prostaglandins is implicated, comprising an amount of the compound of formula (1), or a pharmaceutically acceptable salt thereof, that is effective in treating such disorder or condition, and a pharmaceutically acceptable carrier.
The present invention also relates to a method of treating a disorder or condition in which prostaglandins are implicated as pathogens, in a mammalian subject, which comprises administering to a mammal an amount of compound of formula (I) or a pharmaceutically acceptable salt thereof, that is effective in treating said disorder or medical condition.
The present invention also relates to a method of treating a disorder or condition in a mammal, selected from rheumatoid and osteoarthritis, pyrexia, asthma, bone resorption, cardiovascular diseases, nephrotoxicity, atherosclerosis, hypotension, shock, pain, cancer, Alzheimer disease and other disorders and conditions, in which a pathological role of prostaglandins are implicated, comprising administering to a mammal in need of such treatment an amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof, that is effective in treating such disorder or condition, and a pharmaceutically acceptable carrier.
As used herein, the term xe2x80x9chaloxe2x80x9d means fluoro, chloro, bromo or iodo.
As used herein, the term xe2x80x9calkylxe2x80x9d means straight or branched chain saturated radicals of 1 to 4 carbon atom(s), including, but not limited to, methyl, iso-propyl, tert-butyl, and the like.
As used herein, the term xe2x80x9chalosubstituted alkylxe2x80x9d refers to an alkyl radical as described above substituted with one or more halogen including, but not limited to, trifluoromethyl, and the like.
As used herein, the term xe2x80x9ccycloalkylxe2x80x9d means saturated carbocyclic radicals of 3 to 8 carbon atoms, including, but not limited to, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
As used herein, the term xe2x80x9ccycloalkenylxe2x80x9d means carbocyclic unsaturated radicals of 4 to 8 carbon atoms, including, but not limited to, cyclopentyl, cyclohexyl, cyclohexenyl.
As used herein, a 5-membered monocyclic aromatic ring usually has one heteroatom selected from O, S and N. In addition to said heteroatom, the monocyclic aromatic ring may optionally have up to three N atoms. The 5-membered monocyclic aromatic ring includes, but not limited to thiazolyl, furyl, oxazolyl, isooxazolyl, thienyl, isothiazolyl, pyrrolyl, imidazolyl, pyrazolyl, oxadiazolyl, triazolyl, thiadiazolyl, furazanyl and tetrazolyl.
As used herein, a 6-membered monocyclic aromatic ring usually has one heteroatom which is N. In addition to said heteroatom, the monocyclic aromatic ring may optionally have up to four N atoms. The 6-membered monocyclic aromatic ring includes, but not limited to, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl and triazinyl. Preferably, X1 is attached to 3, 4, 5 and 6-positions of the heteroaryl ring and X2 is attached to 4, 5 and 6-positions of the imidazole ring. More preferably, X1 is attached to 6-position of the heteroaryl ring and X2 is attached to 5 and 6-positions of the imidazole ring.
Preferred compounds of this invention are those of the formula (1) wherein
Ar is heteroaryl selected from
a 5-membered monocyclic aromatic ring having one hetero atom selected from O, S and N and optionally containing one or two N atom(s) in addition to said hetero atom, or
a 6-membered monocyclic aromatic ring having one N atom and optionally containing one to three N atom(s) in addition to said N atom; and
X1 is independently selected from halo, C1-C4 alkyl, hydroxy, C1-C4 alkoxy, halo-substituted C1-C4 alkyl, hydroxy-substituted C1-C4 alky, (C1-C4 alkoxy)C1-C4 alkyl, halo-substituted C1-C4 alkoxy, amino, Nxe2x80x94(C1-C4 alkyl)amino, N,N-di(C1-C4 alkyl)amino, Nxe2x80x94(C1-C4 alkanoyl)amino, C1-C4 alkanoyl, carboxy, carbamoyl, [Nxe2x80x94(C1-C4 alkyl)amino]carbonyl, [N,N-di(C1-C4 alkyl)amino]carbonyl, cyano, nitro, mercapto and (C1-C4 alkyl)thio;
X2 is independently selected from halo, C1-C4 alkyl, hydroxy, C1-C4 alkoxy, halo-substituted C1-C4 alkyl, hydroxy-substituted C1-C4 alkyl, (C1-C4 alkoxy)C1-C4 alkyl, halo-substituted C1-C4 alkoxy, amino, Nxe2x80x94(C1-C4 alkyl)amino, N,N-di(C1-C4 alkyl)amino, Nxe2x80x94(C1-C4 alkanoyl)amino, [(C1-C4 alkyl)sulfonyl]amino, C1-C4 alkanoyl, carboxy, carbamoyl, N-carbamoylamino, cyano, nitro, mercapto and (C1-C4 alkyl)thio;
R1 is selected from
hydrogen;
straight or branched C1-C4 alkyl optionally substituted with one to three substituent(s) wherein said substituents are independently selected from halo, hydroxy, C1-C4 alkoxy and amino;
C3-C8 cycloalkyl optionally substituted with one to three substituent(s) wherein said substituents are independently selected from halo, C1-C4 alkyl, hydroxy, C1-C4 alkoxy and amino;
C4-C8 cycloalkenyl optionally substituted with one to three substituent(s) wherein said substituents are independently selected from halo, C1-C4 alkyl, hydroxy, C1-C4 alkoxy, amino, Nxe2x80x94(C1-C4 alkyl)amino and N,N-di(C1-C4 alkyl)amino;
phenyl optionally substituted with one to three substituent(s) wherein the substituents are independently selected from halo, C1-C4 alkyl, hydroxy, C1-C4 alkoxy, halo-substituted C1-C4 alkyl, hydroxy-substituted C1-C4 alkyl, (C1-C4 alkoxy)C1-C4 alkyl, halo-substituted C1-C4 alkoxy, amino, (C1-C4 alkanoyl)amino, C1-C4 alkanoyl, carboxy, carbamoyl, (C1-C4 alkyl)thio, (C1-C4 alkyl)sulfinyl, (C1-C4 alkyl)sulfonyl, and aminosulfonyl; or
heteroaryl selected from
a 5-membered monocyclic aromatic ring having one hetero atom selected from O, S and N and optionally containing one or two N atom(s) in addition to said hetero atom; or
a 6-membered monocyclic aromatic ring having one N atom and optionally containing one to three N atom(s) in addition to said N atom; wherein
said heteroaryl being optionally substituted with one to three substituent(s) selected from X1 of this claim;
R2 and R3 are independently selected from:
hydrogen;
halo;
C1-C4 alkyl;
phenyl optionally substituted with one to three substituent(s) wherein the substituents are independently selected from halo, C1-C4 alkyl, hydroxy, C1-C4 alkoxy, amino, Nxe2x80x94(C1-C4 alkyl)amino and N,N-di(C1-C4 alkyl)amino;
or R1 and R2 can form, together with the carbon atom to which they are attached, a C5-C7 cycloalkyl ring;
m is 0, 1, 2, 3 or 4 and
n is 0, 1, 2 or 3.
More preferred compounds of this invention are those of formula (I), wherein
Ar is selected from
a 5-membered monocyclic aromatic ring having one hetero atom selected from O, S and N and optionally containing one N atom in addition to said hetero atom, or
a 6-membered monocyclic aromatic ring having one N atom and optionally containing one or two N atom(s) in addition to said N atom; and
X1 is selected from halo, C1-C4 alkyl, halo-substituted C1-C4 alkyl, C1-C4 alkoxy, halo-substituted C1-C4 alkoxy, carbamoyl, [Nxe2x80x94(C1-C4 alkyl)amino]carbonyl, [N,N-di(C1-C4 alkyl)amino]carbonyl and cyano;
X2 is selected from halo, C1-C4 alkyl, hydroxy, C1-C4 alkoxy, halo-substituted C1-C4 alkyl, hydroxy-substituted C1-C4 alkyl, halo-substituted C1-C4 alkoxy, amino, Nxe2x80x94(C1-C4 alkyl)amino, N,N-di(C1-C4 alkyl)amino, N-formylamino, Nxe2x80x94(C1-C4 alkanoyl)amino, [(C1-C4 alkyl)sulfonyl]amino, N-carbamoylamino, cyano and nitro; and
R1 is selected from
C1-C4 alkyl optionally substituted with one to three substituents wherein said substituents are independently selected from halo, hydroxy and amino;
C5-C7 cycloalkyl optionally substituted with one to three substituents wherein said substituents are independently selected from halo, hydroxy and amino;
phenyl optionally substituted with one or two substituent(s), said substituents being independently selected from halo, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, halo-substituted C1-C4 alkyl, halo-substituted C1-C4 alkoxy, (C1-C4 alkyl)thio, C1-C4 alkylsulfonyl and amino; or
heteroaryl optionally substituted with one or two C1-C4 alkyl group(s), wherein said heteroaryl being selected from
a 5-membered monocyclic aromatic ring having one hetero atom selected from O, S and N and optionally containing one N atom in addition to said hetero atom, or
a 6-membered monocyclic aromatic ring having one N atom and optionally containing one or two N atom(s) in addition to said N atom;
R2 and R3 are independently selected from
hydrogen;
halo;
C1-C4 alkyl; and
phenyl optionally substituted from halo, hydroxy, amino, C1-C4 alkyl and C1-C4 alkoxy;
or R1 and R2 can form, together with the carbon atom to which they are attached, a C5-6 cycloalkyl ring;
m is 0, 1, 2 or 3; and
n is 0, 1, or 2.
More preferred compounds of this invention are those of formula (I), wherein
Ar is selected from pyridyl, pyrimidinyl, pyrazinyl thiazolyl, furyl, oxazolyl, isooxazolyl, thienyl, thiazolyl, isothiazolyl, pyrrolyl, imidazolyl, pyrazolyl and pyridazinyl;
X1 is selected from halo, C1-C4 alkyl, halo-substituted C1-C4 alkyl, C1-C4 alkoxy, carbamoyl and cyano;
X2 is selected from halo, C1-C4 alkyl, hydroxy, C1-C4 alkoxy, halo-substituted C1-C4 alkyl, halo-substituted C1-C4 alkoxy, amino, Nxe2x80x94(C1-C4 alkyl)amino, N,N-di(C1-C4 alkyl)amino, N-formylamino, Nxe2x80x94(C1-C4 alkanoyl)amino, [(C1-C4 alkyl)sulfonyl]amino, N-carbamoylamino, cyano and nitro;
R1 is selected from
straight or branched C1-C4 alkyl;
C5-C7 cycloalkyl;
phenyl optionally substituted with one or two substituent(s), said substituents being independently selected from halo, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, halo-substituted C1-C4 alkyl, (C1-C4 alkyl)thio and C1-C4 alkylsulfonyl; or
heteroaryl optionally substituted with one or two C1-C4 alkyl group(s), said heteroaryl being selected from pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolyl, furyl, oxazolyl, isooxazolyl, thienyl, thiazolyl, isothiazolyl, pyrrolyl, imidazolyl and pyrazolyl;
R2 is selected from hydrogen, C1-C4 alkyl and phenyl;
R3 is selected from hydrogen, halo, C1-C4 alkyl and cyano; or R1 and R2 can form, together with the carbon atom to which they are attached, cyclohexyl; and
m is 0, 1 or 2.
Particularly preferred compounds of this invention are those of formula (I), wherein
Ar is heteroaryl selected from pyridyl, pyrimidinyl, pyrazinyl and thiazolyl;
X1 is selected from fluoro, chloro, methyl, methoxy, trifluoromethyl, carbamoyl and cyano;
X2 is selected from fluoro, methyl, hydroxy, methoxy, ethoxy, isopropoxy, trifluoromethyl, trifluoromethoxy, amino, N-methylamino, N,N-dimethylamino, N-methylsulfonylamino, N-formylamino, N-acetylamino, N-carbamoylamino, cyano and nitro;
R1 is selected from methyl, isopropyl, cyclohexyl, phenyl, furyl, thienyl, pyridyl, imidazolyl and thiazolyl which are optionally substituted with one to three substituents selected from methyl, ethyl, isopropyl, methoxy, ethoxy, fluoro, chloro and hydroxy;
R2 is selected from hydrogen, methyl and phenyl; or R1 and R2 can form, together with the carbon atom to which they are attached, cyclohexyl;
R3 is selected from hydrogen, fluoro and cyano; and
m is 0 or 1.
Among the compounds of formula (I), particularly preferred individual compounds are one of the following:
(E)-1-(2-Pyridyl)-2-styryl-1H-benzimidazole or salts thereof;
(E)-1-(4-Pyridyl)-2-styryl-1H-benzimidazole or salts thereof;
(E)-1-(2-Pyrimidyl)-2-styryl-1H-benzimidazole oxalate or salts thereof;
(E)-2-(2-Fluorostyryl)-1-(2-pyridyl)-1H-benzimidazole hydrochloride;
(E)-2-(2,6-Difluorostyryl)-1-(2-pyridyl)-1H-benzimidazole hydrochloride;
(E)-2-[2-(Cyclohexyl)ethenyl]-1-(2-pyridyl)-1H-benzimidazole or salts thereof;
(E)-2-[2-(3-Furyl)ethenyl]-1-(2-pyridyl)-1H-benzimidazole or salts thereof;
(E)-1-(2-Pyridyl)-2-[2-(2-thienyl)ethenyl]-1H-benzimidazole or salts thereof;
(E)-5-Methyl-1-(2-pyridyl)-2-styryl-1H-benzimidazole or salts thereof;
(E)-5-Fluoro-1-(2-pyridyl)-2-styryl-1H-benzimidazole or salts thereof;
(E)-1-(2-Pyridyl)-2-styryl-5-methoxy-1H-benzimidazole oxalate;
(E)-2-[2-(Cyclohexyl)ethenyl]-5-methyl-1-(2-pyridyl)-1H-benzimidazole oxalate;
(E)-2-[2-(3-Furyl)ethenyl]-5-methyl-1-(2-pyridyl)-1H-benzimidazole oxalate;
(E)-5-Methyl-1-(2-pyridyl)-2-[2-(2-thienyl)ethenyl]-1H-benzimidazole oxalate;
(E)-2-[2-(Cyclohexyl)ethenyl]-5-fluoro-1-(2-pyridyl)-1H-benzimidazole or salts thereof;
(E)-2-[2-(3-Furyl)ethenyl]-1-(2-pyridyl)-5-methoxy-1H-benzimidazole oxalate; and
(E)-5-Methoxy-2-[2-(2-methyl-3-furyl)ethenyl]-1-(2-pyridyl)-1H-benzimidazole or salts thereof
Most preferred individual compounds of this invention are one of the following:
(E)-2-[2-(Cyclohexyl)ethenyl]-1-(2-pyridyl)-1H-benzimidazole or salts thereof;
(E)-5-Fluoro-1-(2-pyridyl)-2-styryl-1H-benzimidazole or salts thereof;
(E)-1-(2-Pyridyl)-2-styryl-5-methoxy-1H-benzimidazole oxalate;
(E)-5-Methyl-1-(2-pyridyl)-2-[2-(2-thienyl)ethenyl]-1H-benzimidazole oxalate;
(E)-2-[2-(Cyclohexyl)ethenyl]-5-fluoro-1-(2-pyridyl)-1H-benzimidazole or salts thereof; and
(E)-5-Methoxy-2-[2-(2-methyl-3-furyl)ethenyl]-1-(2-pyridyl)-1H-benzimidazole or salts thereof.
A compound of formula I may be prepared by any synthetic procedure applicable to structure-related compounds known to those skilled in the art. The following representative examples as described in Schemes I-VI are illustrative of the invention in which, unless otherwise stated, Ar, R1, R2, R3, X1, X2, m and n are as defined herein before. For the synthesis of compounds of related-structure to compounds of the present invention, sec xe2x80x9cBenzimidazoles and Congeneric Tricyclic Compoundsxe2x80x9d in Heterocyclic Compounds, Vol. 40, Preson, P. N. Ed., John Wiley and Sons, NY, 1981. 
For example, the compound of formula I may be prepared according to the reaction outlined in Scheme A. In the instant example, a phenylenediamine compound of formula 1 is reacted with a compound of formula 2 wherein the group Q is defined such that the compound of formula 2 is, but not limited to, a carboxylic acid, a carboxylic acid ester, a carboxamide, a carboxylic acid anhydride, a carboxylic acid chloride, an orthoester, an imino ether or a carboxaldehyde. The reaction may be conducted in the presence or absence of a reaction inert solvent. Preferred reaction inert solvents include, but are not limited to, benzene, toluene, xylene, pyridine, 1,2-dichloroethane, o-dichlorobenzene, nitrobenzene, dichloromethane and the like. Preferably, the reaction is conducted in the presence of a promoter such as hydrochloric acid, polyphosphoric acid, phosphorous pentoxide, phosphorous oxychloride, polyphosphoric acid ethyl ether, polyphosphoric acid trimethylsilyl ether, p-toluenesulfonic acid, zinc (II) chloride and the like. When a compound of formula 2 is carboxaldehyde, the reaction may be conducted in the presence of an oxidant such as cupric acetate, chloranil, and the like. Reaction temperatures are preferably in the range of xe2x88x9240xc2x0 C. to 250xc2x0 C., more preferably 10xc2x0 C. to 200xc2x0 C., usually in the range of room temperature (e.g., 25xc2x0 C.) to 200xc2x0 C., but if necessary, lower or higher temperature can be employed. Reaction times are, in general, from 1 minute to several days, preferably from 20 minutes to 1 day. Alternatively, the reaction may be conducted in a sealed tube or an autoclave at medium to high pressure to accelerate it, preferably in the range of 2 to 150 kg/cm2. 
Alternatively, the compounds of formula I may be prepared by a two step procedure from phenylenediamine compounds of formula 1 via the (N-acylamino)phenylamine compounds of formula 4 as shown in Scheme B. In the first step, a phenylenediamine compound of formula 1 is reacted with a compound of formula 3, wherein Z is selected from halo, xe2x80x94OH, xe2x80x94OR (R is C1-C4 alkyl), xe2x80x94NH2 or xe2x80x94OC(O)CR2xe2x95x90CR3xe2x80x94R1, by conventional methods known to those skilled in the art to form amides of formula 4. For example, when a compound of formula 3 is carboxylic acid (i.e., Z is OH), the reaction is preferably conducted in the presence of a coupling reagent such as 1-(dimethylaminopropyl)-3-ethylcarbodiimide (WSC), N,Nxe2x80x2-dicyclohexylcarbodiimide (DCC), carbonyldiimidazole, cyanophosphonic acid diethyl ester or the like. Preferred reaction-inert solvents include, but are not limited to, acetone, acetonitrile, dichloromethane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, dioxane, tetrahydrofuran and pyridine. Reaction temperatures are preferably in the range of xe2x88x9240xc2x0 C. to 250xc2x0 C., more preferably 10xc2x0 C. to 200xc2x0 C., usually in the range of room temperature (e.g., 25xc2x0 C.) to 200xc2x0 C., but if necessary, lower or higher temperature can be employed.
In the next step, the compounds of formula I are provided by cyclization of the compounds of formula 4. The reaction may be conducted in the presence or absence of a reaction inert solvent. Preferred reaction inert solvents include, but are not limited to, benzene, toluene, xylene, pyridine, 1,2-dichloroethane, o-dichlorobenzene, nitrobenzene, dichloromethane and ethanol. Preferably, the reaction is conducted in the presence of a promoter such as of hydrochloric acid, polyphosphoric acid, phosphorous pentoxide, phosphorous oxychloride, polyphosphoric acid ethyl ether, polyphosphoric acid trimethylsilyl ether, thionyl chloride and p-toluenesulfonic acid. Alternatively, the cyclization reaction may be performed under Mitsunobu-type reaction conditions, for example, in the presence of triphenylphosphine and diethyl azodicarboxylate (DEAD). Reaction temperatures are preferably in the range of xe2x88x9240xc2x0 C. to 250xc2x0 C., more preferably 10xc2x0 C. to 200xc2x0 C., usually in the range of room temperature (e.g., 25xc2x0 C.) to 200xc2x0 C., but if necessary, lower or higher temperature can be employed Reaction times are, in general, from 1 minute to several days, preferably from 20 minutes to 1 day. 
In another embodiment, the compounds of formula Ixe2x80x2 may be prepared as shown in Scheme C. Thus, 2-methylbenzimidazole compounds of formula 5 are reacted with aldehydes of formula 6 in the presence or absence of base (Sanfilippo, P. J.; Urbanski, M.; Press, J. B.; Hajos, Z. G.; Shriver, D. A.; Scott, C. K. J Med Chem., 1988, 31, 1778). When the said reaction is conducted in the absence of base, the reaction is preferably performed in a sealed tube or an autoclave at medium to high pressure, preferably in the range of 2 to 150 kg/cm2. The reaction may be conducted in the presence or absence of a reaction inert solvent. Preferred reaction inert solvents include, but are not limited to, benzene, toluene, xylene, chlorobenzene, nitrobenzene, acetic acid, acetic anhydride. Reaction temperatures are generally in the range of xe2x88x92100xc2x0 C. to 250xc2x0 C., preferably in the range of room temperature (e.g., 25xc2x0 C.) to 200xc2x0 C., but if necessary, lower or higher temperature can be employed. Reaction times are, in general, from 1 minute to a day, preferably from 20 minutes to 5 hours, however shorter or longer reaction times if necessary can be employed. When the said reaction is conducted in the presence of base, reaction temperatures are generally in the range of xe2x88x92100xc2x0 C. to 250xc2x0 C., preferably in the range of xe2x88x9280xc2x0 C. to room temperature(e.g., 25xc2x0 C.), but if necessary, lower or higher temperature can be employed. Preferred reaction inert solvents include, but are not limited to, THF, benzene, toluene, xylene. Reaction times are, in general, from several minutes to a day, preferably from 20 minutes to 5 hours, however shorter or longer reaction times, if necessary, can be employed. A preferred base is selected from, for example, but not limited to, an alkali or alkaline earth metal hydroxide, alkoxide, carbonate, or hydride, such as sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate, sodium hydride or potassium hydride, or an amine such as triethylamine, diisopropylamine, diisopropylethylamine, piperidine or dimethylaminopyridine, or an alkyl lithium such as n-butyl lithium, sec-butyl lithium, tert-butyl lithium, methyl lithium or lithium diisopropylamide. 
The compounds of formula I may also be prepared by reacting a compound of formula 7 with a compound of formula 8 according to the procedure outlined in Scheme D. In Scheme D, the compound of formula 7 may be synthesized by any of the methods described in Schemes A to C herein before. The group L of the compounds of formula 8 is a selected from a suitable displaceable group, for example, a halo or sulfonyloxy group such as fluoro, chloro, bromo, iodo, trifluoromethanesulfonyloxy, methanesulfonyloxy or p-toluenesulfonyloxy group, all readily accessible by conventional methods known to those skilled in the art. Preferably, the instant reaction is conducted in the presence of a suitable base, for example, an alkali or alkaline earth metal hydroxide, alkoxide, carbonate, or hydride, such as, but not limited to, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate, sodium hydride or potassium hydride, or in the presence of an organic base an amine such as, but not limited to, triethylamine, diisopropylethylamine diisopropylamine, or dimethylaminopyridine. Preferred reaction-inert solvents include, but are not limited to, acetone, acetonitrile, dichloromethane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide (DMSO), dioxane, tetrahydrofuran and pyridine. Reaction temperatures are preferably in the range of xe2x88x9240xc2x0 C. to 200xc2x0 C., usually in the range of room temperature (e.g., 25xc2x0 C.)to reflux temperature of solvent, but if necessary, lower or higher temperature can be employed. Reaction time is in general from 1 minute to several days, preferably from 30 minutes to 5 days. Conveniently, the reaction may be conducted in the presence of a suitable catalyst, for example, tetrakis(triphenylphosphine)-palladium(0), dichloro bis(triphenylphosphine)palladium (II), copper (0), cuprous oxide, cuprous iodide, cuprous bromide or cuprous chloride. 
Alternatively, the compounds of formula I may be prepared by the reaction of a suitable aldehyde with a suitable phosphonium (Maryanoff, B. E.; Reitz, A. B. Chem. Rev. 1989, 89, 863) or a dialkyl phosphonate salt (Seguineau,; Villieras, Tetrahedron Lett. 1988, 29, 477) as shown in Schemes E and F, wherein P is a suitable phoshonium or dialkyl phosphonate salt. For appropriate references see DE1939809A.
The starting material of formulae 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12 may be obtained by conventional procedures known to those skilled in the art. The preparation of such starting materials is described within the accompanying non-limiting examples which are provided for the purpose of illustration only. Alternatively, requisite starting materials may be obtained by analogous procedures, or modifications thereof described hereinafter.
The products which are addressed in the aforementioned general synthesis and illustrated in the experimental examples herein may be isolated by standard methods and purification can be achieved by conventional means known to those skilled in the art, such as distillation, recrystallization and chromatography techniques.
The compounds of the present invention which contain one or more double bonds and/or asymmetric centers are capable of existing in various steroisomeric forms. All individual forms and mixtures thereof, are included within the scope of the invention. The various isomers can be obtained by standard methods. For example, cis/trans mixtures can be separated into the individual stereoisomers by stereoselective synthesis, or by separation of the mixtures by fractional crystallization or chromatography techniques.
A majority of the compounds of the present invention are capable of forming addition salts with inorganic and organic acids. The pharmaceutically acceptable acid salts of the compounds of the present invention are those which form non-toxic addition salts, such as, but not limited to, the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate or acetate, fumalate, tartrate, succinate, maleate, glucronate, sacchariate, benzoate, methanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i.e., 1,1xe2x80x2-methylene-bis-(2-hydroxy-3-naphthoate)) salts.
The compounds of the invention which have also acidic groups are capable of forming base salts with various pharmaceutically acceptable cations. Examples of such salts include the alkali metal or alkaline earth metal salts and particularly, the sodium or potassium salts. These salts are all prepared by conventional techniques. For example, these salts can be easily prepared by treating the aforementioned compounds with an aqueous solution containing the desired pharmaceutically acceptable cation, and then evaporating the resulting solution to dryness, preferably under reduce pressure. Alternatively, they may be also be prepared by mixing together with a lower alkoxide, and then evaporating the resulting solution to dryness in the same manners as before. In either case, stoichiometric quantities of reagents are preferably employed in order to ensure completeness of reaction and maximum production of yields of the desired final product.
The activity of the compounds of the formula (I) of the present invention, is demonstrated by the following assays.
Human umbilical vein endothelial cells (HUVEC), which is characterized by positive staining with von Willibrand""s factor and an uptake of acetylated low-density lipoproteins, is available from Morinaga Bioscience Lab., Yokohama, Japan. HUVEC is maintained in E-GM UV (from Kurashikibouseki Co., Neyagawa, Japan) in 5% CO2/95% air at 37xc2x0 C. PGE2, thromboxane B2 (TXB2) and 6-keto prostaglandin F1xcex1 (6-keto-PGF1xcex1) are available from Cayman Chemical Co. (Ann Arbor, USA). Recombinant human interleukin-1xcex2 (hIL-1xcex2) is available from RandD Systems (Minneapolis, USA). RIA kits for PGE2, TXB2 and 6-keto-PGF1xcex1 is available from Amersham (Tokyo, Japan). Indomethacin and other reagents used herein are available from Sigma Chemical Co. (St. Louis, USA) unless specified otherwise. Dexamethasone (sold under the trade name of decadron) is available from Banyu Pharmaceutical Co. (Tokyo, Japan). A blood collection tube sold under the trade name of Vacutainer is available from Becton Dickinson (Bedford, USA). Male Sprague-Dawley rats are available from Charles River (Hino, Japan).
Human cell based COX-1 assay is carried out essentially according to a previously described procedure (Grossman et al., Inflam. Res., 1995, 44, 253). Human peripheral blood obtained from healthy volunteers using Vacutainer is diluted to 1/10 volume with 3.8% sodium citrate solution. The platelet-rich plasma immediately obtained is washed with 0.14 M sodium chloride containing 12 mM Tris-HCl (pH 7.4) and 1.2 mM EDTA. Platelets are then washed with platelet buffer (Hanks buffer (Ca free) containing 0.2% BSA and 20 mM Hepes). Finally, the human washed platelets (HWP) are suspended in platelet buffer at the concentration of 2.85xc3x97107 cells/ml and stored at room temperature until use. The HWP suspension (70 xcexcl aliquots, final 2.0xc3x97107 cells/ml) is placed in a 96-well U bottom plate and 10 xcexcl aliquots of 12.6 mM CaCl2 added. Platelets are incubated with A23187 (final concentration; 10 xcexcM, Sigma) with test compound (0.1-100 xcexcM) dissolved in DMSO (final concentration; less than 0.01%) at 37xc2x0 C. for 15 min. The reaction is stopped by addition of EDTA (final concentration; 7.7 mM) and TXB2 in the supernatant quantitated by using a radioimmunoassay kit (Amersham) according to the manufacturer""s procedure.
The human cell based COX-2 assay is carried out as previously described (Moore et al., Inflam. Res., 1996, 45, 54). Confluent human umbilical vein endothelial cells (HUVECs, Morinaga) in a 96-well U bottom plate are washed with 100 xcexcl of RPMI1640 containing 2% FCS and incubated with hIL-1xcex2 (final concentration; 300 U/ml, R and D Systems) at 37xc2x0 C. for 24 hr. After washing, the activated HUVECs are stimulated with A23187 (final concentration; 30 xcexcM ) in Hanks buffer containing 0.2% BSA, 20 mM Hepes and test compound (0.1 nM-100 xcexcM) dissolved in DMSO (final concentration; less than 0.01%) at 37xc2x0 C. for 15 min. 6-keto-PGF1xcex1, stable metabolite of PGI2 (prostaglandin I2), in the supernatant is quantitated after adequate dilution by using a radioimmunoassay kit (Amersham) according to the manufacturer""s procedure.
Confluent human umbilical vein endothelial cells (HUVECs, Morinaga) in a 96-well U bottom plate are washed with 100 xcexcl of RPMI1640 containing 2% FCS and test compound (0.1 nM-100 xcexcM) dissolved in DMSO (final concentration; less than 0.01%), and incubated with hIL-1xcex2 (final concentration; 300 U/ml, R and D Systems) at 37xc2x0 C. for 24 hr. After washing, the HUVECs are stimulated with A23187 (final concentration 30 xcexcM) in Hanks buffer containing 0.2% BSA and 20 mM Hepes at 37xc2x0 C. for 15 min. 6-keto-PGF1xcex1, a stable metabolite of prostaglandin I2 (PGI2), in the supernatant is quantitated after adequate dilution by using a radioimmunoassay kit (Amersham) according to the manufacturer""s procedure.
Male Sprague-Dawley rats (5 weeks old, Charles River Japan) are fasted overnight. A line is drawn using a marker above the ankle on the right hind paw and the paw volume (V0) is measured by water displacement using a plethysmometer (Muromachi). Animals are given orally either vehicle (0.1% methyl cellulose or 5% Tween 80) or a test compound (2.5 ml per 100 g body weight). One hour later, the animals are then injected intradermally with xcex-carrageenan (0.1 ml of 1% w/v suspension in saline, Zushikagaku) into right hind paw (Winter et al., Proc. Soc. Exp. Biol. Med, 1962, 111, 544; Lombardino et al., Arzneim. Forsch., 1975, 25, 1629) and three hours later, the paw volume (V3) is measured and the increase in volume (V3-V0) calculated. Since maximum inhibition attainable with classical NSAIDs is 60-70%, ED30 values are calculated.
Determination of PGE2 synthesized in the inflammatory site is carried essentially according to a previously described method (Opas et al., Biochem. Pharmacol, 1987, 36, 547). Foot edema in male Sprague-Dawley rats (5 weeks old) is induced by subplanter injection of 0.1 ml of 1% w/v xcex-carrageenan suspension. Animals are sacrificed by cervical dislocation 3 h following carrageenan injection. The foot is amputated, frozen in liquid nitrogen and stored at xe2x88x9280xc2x0 C. until analysis. The stomach of these animals are excised, frozen in liquid nitrogen and stored at xe2x88x9280xc2x0 C. until analysis. The frozen foot is crushed, mixed with 7 ml of ethanol containing 10 xcexcg/ml of indomethacin, pulverized in a Waring blender and clarified by centrifugation at 3,000 r.p.m. for 10 min. at 4xc2x0 C. The frozen stomach is mixed with 7 ml of ethanol containing 10 xcexcg/ml of indomethacin, homogenized by Polytrone and clarified by centrifugation at 3,000 r.p.m. for 10 min. at 4xc2x0 C. PGE2 is extracted by a solid-phase extraction devices sold under the trade name of Sep-Pak C18 cartridge (from Waters, Milford, USA) and dried in vacuum. Samples are diluted to a final volume of 0.5 ml with assay buffer (PBS containing 0.1% w/v gelatin) and the level of PGE2 is quantitated after adequate dilution by using a radioimmunoassay kit (Amersham) according to the manufacturer""s procedure. Test compounds are suspended in 0.1% w/v methylcellulose and dosed 1 h before carrageenan injection. Dexamethasone is dissolved in saline and administered subcutaneously 3 h before carrageenan injection.
The gastric ulcerogenicity of test compound is assessed by a modification of the conventional method (Ezer el al., J. Pharm. Pharmacol, 1976, 28, 655; Cashin et al., J. Pharm. Pharmacol., 1977, 29, 330). Male Sprague-Dawley rats (5 weeks old, Charles River Japan), fasted overnight, are given orally either vehicle (0.1% methyl cellulose or 5% Tween 80) or a test compound (1 ml per 100 g body weight). Six hours after, the animals are sacrificed by cervical dislocation. The stomachs are removed and inflated with 1% formalin solution (10 ml). Stomachs are opened by cutting along the greater curvature. From the number of rats that show at least one gastric ulcer or haemorrhaging erosion (including ecchymosis), the incidence of ulceration is calculated. Animals do not have access to either food or water during the experiment. The half-ulcerogenic dose (UD50) value, i.e., dose required to induce at least one gastric lesion or one hemorrhagic erosion in 50% of the animals tested, is calculated by non-linear equation; % Control=100/(1+[Dose]/UD50).
Statistical program packages, SYSTAT (SYSTAT, INC.) and StatView (Abacus Cencepts, Inc.) for Macintosh were used. Differences between test compound treated group and control group are tested for using ANOVA. The IC50, ED30 or UD50 values are calculated from the equation for the log-linear regression line of concentration (dose) versus percent inhibition.
In these testings, some compounds indicated low IC50 values, in the range of 0.01 to 1.0 xcexcM.
The compounds of the formula (I) of this invention can be administered via either the oral, parenteral or topical routes to mammals. In general, these compounds are most desirably administered to humans in doses ranging from 0.01 mg to 100 mg per kg of body weight per day, although variations will necessarily occur depending upon the weight, sex and condition of the subject being treated, the disease state being treated and the particular route of administration chosen. However, a dosage level that is in the range of from 0.1 mg to 10 mg per kg of body weight per day, single or divided dosage is most desirably employed in humans for the treatment of above-mentioned diseases.
The compounds of the present invention may be administered alone or in combination with pharmaceutically acceptable carriers or diluents by either of the above routes previously indicated, and such administration can be carried out in single or multiple doses. More particularly, the novel therapeutic agents of the invention can be administered in a wide variety of different dosage forms, i.e., they may be combined with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, lozenges, trochees, hard candies, powders, sprays, creams, salves, suppositories, jellies, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups, and the like. Such carriers include solid diluents or fillers, sterile aqueous media and various nontoxic organic solvents, etc. Moreover, oral pharmaceutical compositions can be suitably sweetened and/or flavored. In general, the therapeutically-effective compounds of this invention are present in such dosage forms at concentration levels ranging 5% to 70% by weight, preferably 10% to 50% by weight.
For oral administration, tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dipotassium phosphate and glycine may be employed along with various disintegrants such as starch and preferably corn, potato or tapioca starch, alginic acid and certain complex silicates, together with granulation binders like polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tabletting purposes. Solid compositions of a similar type may also be employed as fillers in gelatine capsules; preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols. When aqueous suspensions and/or elixirs are desired for oral administration, the active ingredient may be combined with various sweetening or flavoring agents, coloring matter or dyes, and, if so desired, emulsifying and/or suspending agents as well, together with such diluents as water, ethanol, propylene glycol, glycerin and various like combinations thereof.
For parenteral administration, solutions of a compound of the present invention in either sesame or peanut oil or in aqueous propylene glycol may be employed. The aqueous solutions should be suitably buffered (preferably pH greater than 8) if necessary and the liquid diluent first rendered isotonic. These aqueous solutions are suitable for intravenous injection purposes. The oily solutions are suitable for intra-articular, intra-muscular and subcutaneous injection purposes. The preparation of all these solutions under sterile conditions is readily accomplished by standard pharmaceutical techniques well-known to those skilled in the art. Additionally, it is also possible to administer the compounds of the present invention topically when treating inflammatory conditions of the skin and this may preferably be done by way of creams, jellies, gels, pastes, ointments and the like, in accordance with standard pharmaceutical practice.
The following examples contain detailed descriptions of the methods of the preparation of compounds of formula I. These detailed descriptions fall within the scope, and serve to exemplify, the above described General Synthetic Procedures which form part of the invention. These detailed descriptions are presented for illustrative purposes only and are not intended as a restriction in thee scope of the invention.